This is a PI-initiated, collaborative, case/control project to systematically identify human copy number polymorphisms (CNPs) that are associated with severe malaria anemia (SMA) and other forms of severe malaria. CNPs represent regions in the genome typically >1kb that differ in the number between normal individuals within the population and that occur in 1% or more of a given population. CNPs are enriched for genes with immune function and there are now a number CNPs associations that have been shown for infectious and autoimmune diseases. To date there has been no large scale study of CNPs for malaria, despite the fact that the extensive number of mutations cataloged affecting malaria still cannot account for the expected variation. We will use a collaboratively developed custom design for array comparative genomic hybridization (aCGH) that densely probes thousands of known CNPs within the human genome allowing us to accurately quantify their copy number and determine if they are associated with SMA. This project is designed to answer the question of whether CNPs account for a significant portion of the genetic variation that increase risk for SMA. To ensure that CNPs in our study populations are well represented, we will first conduct standard array comparative genomic hybridization discovery experiments. We will analyze 72 individuals, representing an equal number of cases and controls, using a commercially-available, high-density tiling microarray (4.2 million probes across the genome). This will identify CNPs within previously under- represented populations such as those found in East Africa that may have not been detected in studies of other human populations. We will then update our custom microarray with the latest set of known CNPs including the newly discovered CNPs. With this array we will type six thousand CNPs in SMA cases (800) and matched controls (800) from NIH and Welcome Trust/MalariaGen funded population-based studies of severe malaria. We will accurately determine CNP copy numbers in each individual and mine this data for associations between individual CNPs and disease status. The validity of these CNPs will be confirmed by replicate locus-specific testing in additional SMA cases and controls sample sets and the generalizability of these findings will be evaluated by testing additional DNA samples from patients with other forms of severe malaria (cerebral malaria and acute respiratory distress). The unique insights gained by this novel approach are expected to fill significant gaps in our understanding of human genetic susceptibility to malaria that will benefit malaria vaccine design strategies aiming to eradicate malaria from the globe.